The bis-indolylmaleimide subunit is present in a number of biologically active metabolites isolated from Streptomycetes including Staurosporine, (Tamaoki et al., Biochem. Biophys. Res. Commun. 135: 397-402 (1986); Gross et al., Biochem. Pharmacol. 40: 343-350 (1990)) and Rebeccamycin, (Steglich et al., Angw Chem. Int. Ed. Engl. 19:459 (1980)). The simplest members of this class of compounds are the arcyriarubins, a family of pigments produced by slime molds (Myxomycetes). Id. Bis-indolylmaleimides are selective inhibitors of PKC and show promise as a novel potential therapy for auto immune diseases (Bit, R. A. et al., J. Med. Chem. 361:21 (1993)). The bisindolylmaleimide GF109303X has been recognized as a PKC kinase selective agent, (Bit, R. A. et al., Tetrahedron Letters 34:5623 (1993)) as has the conformational restricted analog, Ro 32-0432 (Wilkinson, S. E., J. Med. Chem. 36:21 (1993)) and also N,N'bridged bisindolylmaleimide macrocycles (Jirousek et al., J. Med. Chem. 39 (14):2664-2671 (1996)).
Several methods are available in the literature to prepare the bis-indolylmaleimide framework including reaction of dihalomaleimides with indole Grignard reagents (Faul et al., Synthesis 12:1511 (1995) and Steglich, W. Tetradron 44: 2887 (1988)), oxidative coupling of indole-3-acetic acid trianions (Bergman et al., Tetrahedron Letters 28:1444 (1987)), and reaction of indolyl-3-glyoxyl chlorides with either indole-3-acetic acid in a Perkin condensation approach or with indole-3-acetimidates (Specter et al., J. Am. Chem. Soc. 76:6208 (1954); Davis, P. D., et al., Tetrahedron Letters 31:5201 (1990), Bit, R. A., Tetrahedron Letters 34:5623 (1993)) to prepare a bisindolylmaleic anhydride which is then converted to a bisindolylmaleimide in a two-step synthesis. Although all of these procedures can be utilized to prepare bisindolylmaleimides, one must use different procedures or multiple steps to prepare un-symmetrical vs. symmetrically substituted bis-indolylmaleimides. Thus, there remains a need for a general and efficient method of preparing bis-indolylmaleimides.
The present invention provides a general and very efficient method for the synthesis of these substrates. The syntheses provides a flexibile and powerful methodology for the synthesis of bisindolylmaleimides.